David Miliband is stepping down as an MP to take up a charity role in New York.
The former foreign secretary, who was narrowly beaten to the Labour leadership by his brother in 2010.
There had been widespread rumours that he was set for a return to the opposition front bench, with his sibling insisting recently that “the door is open”.
But instead he is expected to quit UK politics altogether, triggering a by-election in his South Shields seat.
Labour MPs expressed sadness at the loss of such a significant figure in what will be seen as a severe blow to the right of the party.
“David will be brilliant over the water as he always is. He’s an inspiration; know he’ll be back in fight one day but for tonight am just sad,” John Woodcock wrote on Twitter.
Toby Perkins said it was “a big loss to British and Labour politics”.
Shadow energy secretary Caroline Flint said she was happy for her former cabinet colleague and his family and made a joke about his new job.
Mr Miliband nicknamed “Brains” by former Number 10 spin chief Alastair Campbell is reported to be joining the International Rescue Committee charity.
“Here’s to International Rescue Thunderbirds are go!”, Ms Flint wrote.
Mr Miliband quit the shadow cabinet after losing the knife-edge vote for the party leadership to his younger brother, saying he did not want to be a “distraction”.
They have admitted that it was a bruising encounter in which David was clear favourite and lost out because Ed secured trade union votes that strained family ties.
He has remained on the backbenches but fuelled talk of a frontline comeback earlier this year with a vocal Commons attack on the Government’s benefit changes.
The MP is married to American violinist Louise Shackelton and the couple have two children.